Approximately 25 million people worldwide are currently suffering from Alzheimer's disease, and that number is expected to double every five years. Studies of the brain tissue of Alzheimer's disease patients have revealed the presence of aggregated peptides, particularly senile plaques and neurofibrillary tangles, which have been reported to be formed from mutated beta-amyloids and Tau peptides (M. Goedert, M. G. Spillantini, Science, 314: 777-784 (2006)). Such aggregated peptides induce cell damage and apoptosis, resulting in neurodegenerative diseases. The presently available methods of symptomatic therapy include the use of acetylcholinesterase inhibitors and NMDA acceptor antagonists, but such agents do not cure the disease.
It has been reported that some inositol stereoisomers prevent beta-amyloids from forming aggregates in in vitro experiments, and also that they are capable of inhibiting the aggregation of beta-amyloids in mouse models of Alzheimer's disease to reduce or alleviate the symptoms of Alzheimer's disease (J. McLaurin et al., Nature Medicine, 12: 801-808 (2006); J. McLaurin et al., J. Biol. Chem. 275: 18495-18502 (2000). However, inositol is known to have difficulty in passing through the blood-brain barrier (BBB), and the amount thereof transferred to the nervous system of the brain is insignificantly small (L. M. Lewin et al., Biochem. Journal, 156: 375-380 (1976); M. Uldry et al., EMBO Journal, 20: 4467-4477 (2000). Hence, in order to apply inositol to the treatment of Alzheimer's disease, a method to enhance the passage of inositol through the BBB must be developed.
Huntington's disease, a neurodegenerative disease inducing dementia, afflicts approximately 30,000 Americans. It has been shown that most Huntington's disease patients have a mutation in the CAG (glutamine codon) repeats of chromosome No. 4, which leads to the production of mutant huntingtin proteins (H. Y. Zoghbi, H. T. Orr, Annu. Rev. Neuroscie., 23: 217-247 (2000). The mutant huntingtin proteins are reported to induce mitochondrial dysfunction in specific nerve cells of the brain, causing the apoptosis of the nerve cells. No therapeutically effective agent for Huntington's disease has been developed.
Trehalose has been reported to efficiently inhibit the polyglutamine-induced aggregate formation in in vivo mouse model experiments, alleviating the symptoms of Huntington's disease (M. Tanaka et al., Nature Medicine, 10: 148-154 (2004). However, it is also known that trehalose cannot pass through the BBB to reach the brain (www.huntingtonproject.org/portals/0/trehalose). Thus, in order to use trehalose as an effective therapeutic agent for Huntington's disease, a method that enables trehalose to pass through the BBB must be developed.
Therefore, the present inventors have endeavored to develop inositol and trehalose derivatives that can pass through the BBB and reach the brain for effective treatment of Alzheimer's disease and Huntington's disease, respectively.